Compulsive drug-seeking and drug-taking behaviors are the hallmark of addiction, and these behaviors continue despite intense negative consequences to the individual. Maladaptive conditioned learning processes, together with molecular and cellular plasticity, play major roles in the development of this compulsive behavior. Addictive drugs including cocaine engage molecular signaling pathways that are involved in associative learning processes. Once learned, exposure to cues previously associated with cocaine can lead to conditioned physiological responses that are accompanied by intense drug craving which can trigger relapse. Hence, a goal of addiction treatment is to break the associations between previously learned positive subjective effects of cocaine and environmental cues that signal cocaine availability. In order to achieve this goal, detailed information is needed about the circuitry and molecular signaling within that circuitry that serves to reinforce and strengthen cocaine reward contextual memories. Glycogen synthase kinase-3beta (GSK3b) is uniquely positioned to regulate neuronal function and plasticity. It is important in dopamine-mediated behaviors and in memory processes, and GSK3 activity is required for cocaine-induced conditioned reward, hyperactivity, and locomotor sensitization. Relevant to relapse, GSK3b is activated by exposure to an environment previously paired with cocaine and, importantly, inhibition of GSK3b activity after reactivation of cocaine memories can abolish a previously established cocaine place preference. This project will address the overall hypothesis that GSK3b signaling is necessary for cocaine-induced reward, neuroplasticity and the reconsolidation of cocaine-associated contextual memories. Using a conditional genetic deletion mouse model, the anatomical and cellular substrates where GSK3b mediates cocaine-induced conditioned reward will be elucidated. Components of the GSK3b signaling pathway that are necessary for cocaine reward and reconsolidation of cocaine memories will be investigated including the downstream effector of GSK3b, the mTORC1 complex. The anatomic substrates of importance for maintenance of cocaine memories will be studied with the focus on a circuit consisting of the dorsal hippocampus to basolateral amygdala to nucleus accumbens. An additional aim will be to extend the studies into a cocaine iv self-administration model in order to investigate if cocaine seeking behaviors can be abolished by inhibition of GSK3 after recall of cocaine memories. Little is known about how the processes governing maintenance of cocaine memories may differ between males and females and hence, investigation of sex differences is another goal of the project. Using these multidisciplinary approaches, we are positioned to reveal molecular mechanisms and pathways underlying cocaine reward, contextual memories, craving and relapse, with the potential of establishing GSK3b as a novel target for therapeutics to prevent relapse to cocaine seeking.